A Systematic Review of the Emerging Treatment for Hepatorenal Syndrome With a Principal Focus on Terlipressin: A Recent FDA-Approved Drug

Background: Hepatorenal syndrome (HRS), a consequence of liver cirrhosis, is the development of renal failure, which carries a grave prognosis. Reversing acute renal failure with various vasoconstrictor therapies at an appropriate time favors a good prognosis, especially when a liver transplant is not feasible. Objective: This study aims to compare various treatment modalities to deduce an effective way to manage HRS. Methods: The authors conducted a literature search in PubMed, Google Scholar, the Cochrane Library, and Science Direct in October 2022, using regular and MeSH keywords. A total of 1072 articles were identified. The PRISMA guidelines were used, the PICO framework was addressed, and the inclusion criteria were set based on studies from the past 10 years. After quality assessment, 14 studies were included for in-depth analysis in this review. Results: A total of 14 studies were included after quality assessment, including randomized controlled trials, systematic reviews, meta-analyses, and observational cohort studies. Nine hundred and forty-one patients represented this review's experimental and observational studies, apart from the other systematic reviews analyzed. Nine studies discovered that Terlipressin, especially when administered with albumin, was more effective than other conventional treatment modalities, including norepinephrine and midodrine, in terms of improving mortality and reversing the HRS. Four studies suggested that terlipressin exhibited similar effectiveness but found no significant difference. In contrast, one study found that norepinephrine was superior to terlipressin when particularly considering the adverse effects. Conclusion: Terlipressin, one of the most widely used vasoconstrictor agents across the world, seems to be effective in reversing renal failure in HRS. Although adverse effects are seen with this agent, it is still beneficial when compared to other medications. Further studies with larger sample sizes may be warranted.


Data Synthesis and Analysis
Among the 1072 articles, 187 duplicates were excluded using EndNote, 885 reports were screened, and 627 were omitted based on the abstract and title, after which 258 reports were sought for retrieval, and 232 reports were omitted due to irrelevancy. The final screening reduced the number of reports to 26, which were evaluated for quality and eligibility. After a thorough reading, 14 eligible reports were included in this study. Two researchers independently extracted and identified data from each study and used the appropriate quality assessment techniques to examine each study's efficacy. When there were differences of opinion, the two researchers considered the study designs, inclusion and exclusion criteria, interventions used, and outcome evaluation to reach a consensus. In ambiguous instances, a third author was brought in to settle disagreements and reach an agreement. A total of 13 reports were eventually included in this study after a thorough investigation. This study did not use any automation tools. Figure 2 depicts the search process used for this review in the form of a PRISMA flow diagram [29].

Discussion
The pathophysiology of HRS is not fully known [30]; however, it is considered a multifactorial triggering event [31,32], where the vascular system plays a crucial role. Cirrhosis gradually increases portal venous resistance, which results in increased blood flow in the splanchnic circulation, further releasing vasodilators, including nitric oxide [30,33], in turn reducing the mean arterial pressure (MAP) and circulatory volume [31]. The fluid retention is brought on by increased anti-diuretic hormone and a decrease in glomerular filtration rate [28]. The declining systemic circulation counter-responses by activating the sympathetic nervous system, the renin-angiotensin-aldosterone system (RAAS) (increasing the circulating angiotensin II levels), and the release of arginine vasopressin, but at the expense of severe constriction of the renal vasculature, which results in a progressive fulminant form of AKI [30,31,[34][35][36].
A liver transplant, the only effective treatment, resolves severe liver disease and portal hypertension, leading to renal recovery. However, only a tiny percentage of HRS patients qualify for timely LTx [31]. HRS can also be treated with various other modalities, including vasoconstrictors, albumin, transjugular intrahepatic portosystemic stent-shunt (TIPSS) [37], and extracorporeal albumin dialysis; however, vasoconstrictors are the most popular approach due to their efficacy and practicality [4,38]. Renal function can be improved by splanchnic vasoconstrictors and albumin therapy, which may also increase short-term waitlist survival [31,39]. Terlipressin causes splanchnic vasoconstriction, which diverts blood to the systemic circulation, lowers the sympathetic nervous system and RAAS activation, decreases the production of arginine vasopressin, and eventually improves kidney perfusion [30,38,[40][41][42][43]. Norepinephrine causes vasoconstriction with minimal effects on the myocardium and corrects the low systemic vascular resistance associated with HRS [41]. Midodrine causes systemic vasoconstriction that, in turn, improves systemic blood pressure and enhances renal perfusion pressure. Octreotide counteracts the effects of several splanchnic vasodilators and decreases the discrepancy in intravascular volume and arterial vasodilation [30,38,[40][41][42][43]. Figure 3 below illustrates the drug nodes versus placebo, presented as high, moderate, low, or very low certainty, with data incorporated from 26 RCTs [3].

FIGURE 3: Depicts various RCTs' drug nodes versus placebo
Original image was created by the authors using Microsoft PowerPoint.
In the absence of terlipressin, norepinephrine use for HRS may be more favorable compared to the conventional combination of octreotide and midodrine. However, norepinephrine frequently necessitates admission to an intensive care or high-dependency facility, which is linked with increased expenditures and resources; hence, octreotide and midodrine are commonly utilized as less expensive alternatives [44]. The persistence of HRS reversal with terlipressin remained until day 30 without renal-replacement therapy (RRT) [42]; this seems therapeutically noteworthy since RRT poses several difficulties for individuals with advanced cirrhosis. It has been hypothesized that terlipressin, by its vasoconstrictor effect, decreases portal inflow [45], protects against bacterial translocation, endotoxemia, and ensuing pro-inflammatory cytokines, which most likely enhances terlipressin's response in patients with decompensated liver cirrhosis [24,42].
The inclusion of the recently released CONFIRM study showed terlipressin to be very beneficial in reversing HRS [3,42]. Compared to the placebo group, the incidence of major adverse events was more significant in the terlipressin group. Potential side effects of terlipressin include abdominal pain, skin discoloration, intestinal ischemia, cardiac ischemia, cyanosis, bradycardia, and diarrhea. The terlipressin group demonstrated increased gastrointestinal bleeding (4% vs. 0%), sepsis (4% vs. 0%), and respiratory failure (10% vs. 3%) compared to the placebo group [42]. Terlipressin's known cardiovascular and pulmonary effects may be responsible for the higher rates of respiratory failure in the terlipressin group compared to the placebo group [42]. Before CONFIRM, most of the terlipressin data came from smaller, nonblinded RCTs with low event rates and unreliable impact estimates [3].
Junior et al. state that in the included trials, only two of the nine cardiovascular events (episodes of segment ST depression) resulted in a change in medication (a titration of dose). The frequencies of adverse events were lower for norepinephrine than terlipressin, as reported in previous studies [4,28,46]. The higher incidence of adverse effects observed in the terlipressin group compared to the norepinephrine group could be explained by three factors. First, the terlipressin dosage was high in studies including people with HRS-documented adverse events because placebo and norepinephrine hardly had any specificity complications [48,49]. Most studies only mentioned terlipressin-specific issues, like abdominal cramps and arrhythmia [4]. Terlipressin can be administered as an intravenous bolus peripherally and hence may be safely administered in regular wards without risk, although it is expensive. But norepinephrine is often administered intravenously as a continuous infusion through a central venous catheter, which requires intensive care unit-level care [28].
The superior effectiveness of terlipressin plus albumin over midodrine and octreotide (MID/OCT) plus albumin in improving renal function may be explained by the more significant effect of terlipressin treatment on increasing MAP [27]. The fact that there were no variations in adverse events between the groups is substantial. Some might counter that in the trial by Sanyal et al., the rate of complete response in the MID/OCT group patients was even lower than that seen with albumin alone [26].
In one study, 50% of all treated patients experienced a recurrence of HRS, while other studies found that relapse rates were between 35% and >50% [25]. The higher recurrence rate after vasoconstrictor withdrawal most likely reflects the fact that HRS type 2 develops in a state of persistent portal hypertension in patients with refractory ascites, as opposed to HRS type 1, which typically develops after an acute complication like infection or GI bleeding with a potentially reversible decompensation of liver and renal function. Relapse patients who underwent retreatment have seen a 43% response rate, corroborating the theory that terlipressin therapy can be used as a stopgap measure before transplant in LTx-eligible patients [25].
Several vasoconstrictors have demonstrated favorable outcomes in the treatment of type 1 HRS; however, there have been relatively few trials on the use of vasopressors in treating type 2 HRS. Terlipressin has been officially approved as one of the mainstay medications to treat HRS. The United States Food and Drug Administration (FDA) recently approved terlipressin injections in adults with HRS with a rapid reduction in kidney function. Terlipressin, to date, remains the first FDA-approved medication for this condition [18]. The risk of severe or fatal respiratory failure increases with terlipressin. Patients with low blood oxygen levels shouldn't be started on this drug [50]. Using a pulse oximeter while receiving this therapy is essential, and clinicians must remain vigilant for patients for breathing issues [1,18,50].

Limitations
Due to the inability to assess the complete text, few studies were excluded; however, the comparison between different treatment options was analyzed. Since the authors included a worldwide search, the method of practicing and diagnosing HRS could have been different across hospitals worldwide. The initiation of treatment could not be studied in depth due to this limitation. Other limitations include the lack of a control group in the observation study, the RCT's small sample size, and minimal information on adverse effects. The mortality estimate is likely confounded by eligibility and the receipt of a liver transplant.

Conclusions
HRS ultimately leads to fluid overload, secondary infection, and organ damage, which may even be fatal without treatment. When a liver transplant is not feasible, medical management is the ultimate resort. Terlipressin seems to be effective in reversing renal failure in HRS and may even decrease mortality. Although adverse effects are seen with this agent, it still seems to be beneficial when compared to other conventional medications. However, further studies with larger sample sizes may be warranted, especially since the adverse events are to be explored in depth.

Conflicts of interest:
In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.